Naloxone was approved by FDA in 1971 and first marketed as Narcan® injection for the complete or partial reversal of opioid intoxication. It has subsequently become a multi-source prescription generic drug and is currently manufactured by International Medication Systems, Limited (IMS) and Hospira, Inc. The injection is available in two strengths, 0.4 mg/mL and 1.0 mg/mL. Naloxone injection is approved worldwide and is on the WHO Model list of Essential Medicines as a specific antidote.
Presently, naloxone is a standard inventory item for emergency services personnel to carry in ambulances and medication kits for reversal of suspected opioid overdose in the pre-hospital setting. Hospital emergency departments also use this medication routinely for this purpose. The initial parenteral dose of naloxone for adults with known or suspected narcotic overdose is 0.4 to 2 mg, which may be repeated as needed to a total dose of 10 mg. The currently available formulations of naloxone are approved for intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration. Naloxone is also indicated as a reversal agent when the effects of therapeutic use of opioids are no longer medically necessary, such as in reversal of opioid effects in general anesthesia.
In 2008, poisoning surpassed motor vehicle accidents as the leading cause of “injury deaths” in the United States (Warner 2011). Nearly 90% of poisoning deaths are caused by drugs. During the past 3 decades, the number of drug poisoning deaths increased six-fold from about 6,100 in 1980 to 36,500 in 2008. Of the 36,500 drug poisoning deaths in 2008, 14,800 involved prescription opioid analgesics. Approximately 3,000 deaths also involved heroin overdose (Warner 2011).
In emergency situations, it is known that the onset of action of the IV injection will be faster, so is preferred. Narcan® is a commercially available intravenous formulation of naloxone HCl that is administered to unresponsive opioid users who have overdosed. The shortcomings of this formulation and route of administration are 1) it takes time to establish IV access and this is exacerbated in individuals who have poor veins from frequent injections with dirty needles; 2) that those who are administering the drug are putting themselves at risk from needle-stick injury from an awakening an agitated patient; and 3) the immediate high blood levels are associated with inducing more frequent and severe opioid withdrawal effects. Further, IV administration requires delivery by a trained professional, limiting the use of the drug to a small percentage of the population who can receive EMS care. Naloxone can be given by IM or SC injection, and has a more gradual onset of action because the drug must be absorbed from the muscle or skin. Although naloxone can also be given by IM or SC administration, the utility of delivering naloxone by lay persons using a needle is not common medical practice. There are currently no over-the-counter medications used by lay persons that require needle-based delivery. Thus, an unmet medical need is a needle-free delivery system capable of delivering naloxone in a properly designed product sufficient to achieve therapeutically effective blood levels of naloxone, and that can be used by a lay person accurately under intense emotional and environmental pressure to treat a person suspected of suffering an opioid overdose—most commonly an immediate family member or close acquaintance.
An additional problem with the current standard of care using naloxone to treat drug overdose is that the delivery of naloxone to patients in a state of drug overdose can result in a variety of responses in the drug overdosed patient. Depending on the route administered, naloxone can rapidly reverse the effects of the opioid, and in many instances, can induce instant and severe pain, nausea, vomiting, the occasional seizure, agitation, and/or combativeness. This can be dangerous both to the patient and to the emergency responder. Once awakened, the patient may be in a state of distress and uncertainty. Medical staff and/or the patient handling an unsheathed needle may risk puncture as a result of a disoriented or agitated patient. Thus, administration of a naloxone formulation, which would lessen a sudden reversal as observed using IV administration, is desired.
Finally, the current standard of care for a patient with a suspected opioid intoxication is to support ventilation and administer naloxone either IV, IM, or subcutaneously (SC). A demonstration of unmet medical need is the off-label administration of naloxone injection intranasally. The injection formulation, which is not formulated for intranasal use, has to be given intranasally via a separate mucosal atomizer device using ad hoc methods (Barton 2005, Kelly 2005, Kerr 2008, Merlin 2010, Robertson 2009, Sporer 2007). For example, the San Francisco EMS uses this drug administration technique as a standard-of-care to prevent needle-stick injuries to EMTs. While naloxone injection formulations currently administered intranasally by EMS personnel in the field as an opioid antidote using the FDA-approved parenteral product and a Mucosal Atomization Device (“MAD” device, available from Teleflex and/or LMA), there are numerous drawbacks that detract from the efficacy of the method. These include formulations not suited for intranasal delivery, a lack of a complete device containing naloxone and designed for intranasal delivery, and a lack of compositions specifically designed for manufacture with intranasal devices that do not utilize terminal autoclave sterilization, which can also be stored and conveniently and safely used and transported, a multi-step process to assemble the required elements subject to confusion and error, and which can be stored for long periods of time without causing product damage (i.e., fracturing of a glass container) or naloxone degradation resulting in the formation of 7,8-didehydronaloxone, a substance considered by the FDA to be undesirable/potentially genotoxic.
Further, currently formulations are not designed for nasal delivery However, Dowling, et al, “Population Pharmacokinetics of Intravenous, Intramuscular, and Intranasal Naloxone in Human Volunteers,” Therapeutic Drug Monitoring, 30(4): 490-496 (2008) (hereafter “Dowling”) describes the absorption and pharmacokinetics of a dilute naloxone injection type solution administered intranasally. The bioavailability was only 4%, suggesting that intranasal naloxone absorption is poor and leading a person skilled in the art away from the present invention. In fact, the authors in Dowling concluded that nasal delivery of naloxone was not feasible based on their results.
Due to the increasing need for opioid overdose reversal agents and methods, there is a need in the art for improved compositions and methods of delivery of such compositions. In particular, there is a need for integrating compositions, methods and devices that can allow for an effective reversal of opioid overdose, but which eliminates or minimizes the use of needles. There is further a need for effective formulations and methods of providing such compositions to an individual, for rapid absorption into the nasal mucosa and for reversing opioid overdose, that can be quickly and easily used, but which minimize sudden and severe side effects of rapid reversal of opioid overdose. Formulations having a concentration suited for delivery to and absorption by the naris (i.e., nostril or nasal passage) are also desired. Ideally, product designs are robust for use in many different environments, from austere to clinical environments, be ready to use, easy to understand and administer quickly, and durable and not subject to damage and breakage. Ideally, the formulations have minimal to no formation of 7,8-didehydronaloxone over accelerated or long term stability studies.
Further, there is a need for one-step, needle-free, portable naloxone delivery drug products that contain a sufficiently high concentration of naloxone but are capable of long term storage in a variety of different conditions, such that the naloxone is intact and effective when needed, and safe to deliver to a patient either by a professional or by an untrained layperson. It may be noted that the current use of nasal administration devices are intended for outpatient treatment in non-life threatening situations. In contrast, administration of naloxone for treatment of overdose is generally in the context of a high stress environment, and bystander administration of naloxone by non-medical persons is of questionable effectiveness, as nonmedical bystanders have limited ability and knowledge necessary to administer naloxone effectively. Clark, et al, “A Systematic Review of Community Opioid Overdose Prevention and Naloxone Distribution Programs” J. Addict Med 2014; 8: 153-163. Thus, a need in the art is for devices and formulations that can be easily administered by non-medical personnel.
The instant disclosure seeks to address one or more of these unmet needs in the art.